Adenosine is a well-known component of several endogenous molecules (ATP, NAD+, nucleic acids). Besides, it plays an important regulatory role in many physiological processes. The effect of adenosine on heart function was discovered already in 1929. (Drury and Szentgyörgyi, J Physiol 68:213, 1929). The identification of an increasing number of physiological functions mediated by adenosine and the discovery of new adenosine receptor subtypes give possibilities for therapeutic application of specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6:619, 1998).
To date, the receptors for adenosine have been classified into three main classes: A1, A2 and A3. The A1 subtype is partly responsible for the inhibition of the adenylate cyclase by coupling to Gi membrane protein, partly influences other second messenger systems. The A2 receptor subtype can be subdivided into two further subtypes—A2a and A2b, which stimulate the adenylate cyclase activity. The sequence of adenosine A3 receptors have been recently identified from rat testis cDNA library. Later it was proved that it corresponds to a novel, functional adenosine receptor. The activation of the A3 receptors is connected also with several second-messenger systems: inhibiting of adenylate cyclase, stimulating phospholipase C and D.
The adenosine receptors are found in several organs and regulate their functions. Both A1 and A2a receptors play important role in the central nervous system and cardiovascular system. In the CNS, the adenosine inhibits the release of synaptic transmitters which effect is mediated by A1 receptors. In the heart, also the A1 receptors mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. The adenosine A2a receptors, which are located in a relatively high amount in the striatum, display functional interaction with the dopamine receptors in regulating the synaptic transmission. The A2a adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.
On the basis of mRNA identification, the A2b adenosine receptors are widely distributed in different tissues. They have been identified almost in every cell type, but its expression is the highest in the intestine and the bladder. This subtype probably also has important regulatory function in the regulation of the vascular tone and plays a role in the function of mast cells.
Contrary to A1 and A2a receptors, where the tissue distribution was detected on the protein level, the presence of A2b and A3 receptors was detected on the basis of their mRNA level. Expression levels for A3 adenosine receptors are rather low compared to other subtypes and are highly species dependent. A3 adenosine receptors are expressed primarily in the central nervous system, testis and immune system, and appear to be involved in the modulation of mediator release from mast cells in immediate hypersensitivity reaction.
The A3 antagonists published so far in the literature belong to the groups of flavonoides, 1,4-dihydropyridine derivatives, triazoloquinazolines, thiazolonaphthyridines and thiazolopyrimidines. The present invention relates to a novel type of effective A3 antagonists, which have the aminoquinoline structure.
For therapeutic use it is essential to ensure that the molecule does not bind, or bind only in the case of very high concentration, to the A1, A2a and A2b sub-types of the adenosine receptor. Our present invention relates to the compounds of the general formula (I) as well as their salts, solvates and isomers, which have great selectivity for the A3 sub-type of the adenosine receptor.
Our aim was to prepare A3 ligands, within them preferably antagonists, first of all with quinoline structure, which exert strong antagonistic effect and high selectivity for the A3 receptor, i.e. they inhibit the A3 receptor in much lower concentration than they inhibit the A1, A2a and A2b receptors. Further aims were to have stability, bioavailability, therapeutic index and toxicity data, enabling these new compounds to develop into drug substances, and that the new compounds possess favourable enteric absorption to be applied orally.